Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease

Annu Rev Genomics Hum Genet. 2014;15:173-94. doi: 10.1146/annurev-genom-091212-153412.


Cholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources through the uptake of low-density lipoproteins. Cholesterol biosynthesis is a complex, multienzyme-catalyzed pathway involving a series of sequentially acting enzymes. Inherited defects in genes encoding cholesterol biosynthetic enzymes or other regulators of cholesterol homeostasis result in severe metabolic diseases, many of which are rare in the general population and currently without effective therapy. Historically, these diseases have been viewed as discrete disorders, each with its own genetic cause and distinct pathogenic cascades that lead to its specific clinical features. However, studies have recently shown that three of these diseases have an unanticipated mechanistic convergence. This surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.

Keywords: Niemann–Pick disease type C; Smith–Lemli–Opitz syndrome; Tangier disease; cholesterol; sphingolipids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / pathology
  • Antley-Bixler Syndrome Phenotype / genetics
  • Antley-Bixler Syndrome Phenotype / pathology
  • Cholesterol / biosynthesis
  • Cholesterol / genetics
  • Cholesterol / metabolism*
  • Chondrodysplasia Punctata / genetics
  • Chondrodysplasia Punctata / pathology
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / pathology
  • Homeostasis*
  • Humans
  • Ichthyosiform Erythroderma, Congenital / genetics
  • Ichthyosiform Erythroderma, Congenital / pathology
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / pathology
  • Lipid Metabolism, Inborn Errors / genetics
  • Lipid Metabolism, Inborn Errors / pathology
  • Lipoproteins, LDL / genetics
  • Lipoproteins, LDL / metabolism*
  • Osteochondrodysplasias / genetics
  • Osteochondrodysplasias / pathology
  • Oxidoreductases Acting on CH-CH Group Donors / deficiency
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Steroid Metabolism, Inborn Errors / genetics
  • Steroid Metabolism, Inborn Errors / pathology


  • Lipoproteins, LDL
  • Cholesterol
  • Oxidoreductases Acting on CH-CH Group Donors

Supplementary concepts

  • Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects
  • Desmosterolosis
  • HEM dysplasia
  • Lathosterolosis